EP0866792B1 - Process for preparing a crystalline polymorph of terazosin hydrochloride - Google Patents

Abstract

A crystalline polymorphous terazosine monohydrochloride is obtained by suspending and treating a crystalline addition product of terazosine hydrochloride and methanol in a polar solvent which is an alcohol with 2 to 6 carbon atoms or a ketone with 2 to 6 carbon atoms or a mixture thereof. The thus obtained crystalline polymorphous terazosine hydrochloride is characterized by a reduced hygroscopicity and solvent residue retention capacity.

Description

The invention relates to a method for producing a crystalline polymorph of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-tetrahydrofuroyl) piperazine monohydrochloride, abbreviated as terazosin hydrochloride.

The compound 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-tetrahydrofuroyl) piperazine is under the general Known as Terazosin. For the monohydrochloride this Compound are several different anhydrous crystal forms (Polymorphs), a crystalline dihydrate form as well a crystalline adduct with methanol is known. This connection and their different polymorphs stand out pharmaceutical applications, e.g. as blood pressure lowering active ingredient.

Japanese patent application JP-A-05-78352 describes several crystal forms of terazosin hydrochloride and their manufacturing routes. One designated there as A-2 crystalline polymorph is due to a powder X-ray diffraction spectrum with characteristic peaks at 7 °, 12 °, 20.3 ° and a doublet at 24.0 ° and should identical to the product of the method according to the invention his. It is manufactured according to this document as follows: First, the free terazosin base is made. This is in the crystalline methanol adduct of their hydrochloride transferred. Then the crystal methanol is dried removed, temperatures around 110 ° C necessary are. The largely methanol-free, very obtained hygroscopic connection is made by treatment with ethanol or mixtures of ethanol and methylene chloride in the desired little hygroscopic crystalline polymorph transferred.

The crystalline polymorph to which the invention relates is also in the unpublished EP-0 708 104 A1 and is referred to there as "Form IV". In the manufacturing process proposed in this document becomes N- (2-tetrahydrofuroyl) piperazine, (Its production by hydrogenating N- (2-furoyl) piperazine is already known from US-A-4 026 894) 4-amino-2-chloro-6,7-dimethoxy-quinazoline coupled, and through a treatment that involves boiling for several hours comprises a high boiling solvent, whereby the Terazosin hydrochloride in crystal form IV is obtained. This The product is then converted to the dihydrate and dried. There is a disadvantage to this method in that it is a multi-hour cooking in a high-boiling Solvents (e.g. methoxyethanol, the health is not harmless), which inevitably causes contamination arise and an undesirable darkening entry. The crystal form IV does not fall in the for pharmacological application desired optimal purity , but requires subsequent treatment (Dihydrate formation), which causes a cleaning, in addition treatment with diatomaceous earth is carried out.

Other crystalline polymorphs of terazosin hydrochloride and their manufacturing processes are described in US-A-5,294,615 and US-A-5,362,730 (corresponding to EP-A-0 623 612) and in US-A-5,412,095 and are described there as Form II and Form III designated and each by the characteristic Peaks marked by their powder X-ray diffraction spectra.

The invention has for its object to provide a method with which the already under the designation A-2 Form IV known crystalline polymorph of terazosin hydrochloride in a particularly simple manner and in particular pure form can be obtained.

The object is achieved by the manufacturing method specified in claim 1 solved.

The method according to the invention is based on the stable method crystalline adduct of terazosin hydrochloride and methanol, which with organic polar solvents or Solvent mixtures from the family of alcohols and Ketones, without prior drying, is treated. It has been shown that methanol-wet methanol adduct, just as it is produced, without Disadvantage can be used and that the residual methanol content of the final product in one for pharmacological Applications still maintains a reasonable framework.

A major advantage of the method according to the invention compared to the above-mentioned known from JP-A-05-78352 The process is thus that the intermediate drying at Temperatures around 110 ° C are not applicable. This intermediate drying step the known method has two major disadvantages. On the one hand, drying creates a very hygroscopic Connection. On the other hand, it can take several hours thermal load at the drying temperatures to begin with Decomposition of the product and thus the emergence of contaminants, leading to the use of the Product as a pharmaceutical ingredient is disadvantageous. These disadvantages are avoided by the method according to the invention.

The crystalline produced by the process according to the invention Polymorph has compared to other anhydrous polymorphs of Terazosin Hydrochloride essential advantages. It is characterized by lower hygroscopicity as well due to a lower retention capacity for residual solvents from what for use as a pharmacological Active ingredient is of great advantage.

An embodiment of the manufacturing method according to the invention is described below.

1. Preparation of the crystalline adduct from terazosin hydrochloride and methanol.

37.6g 4-amino-2- (1-piperazinyl) -6,7-dimethoxyquinazoline and 15.8 g of triethylamine are placed in 400 ml of methylene chloride. The suspension is cooled to -5 ° C. With stirring 21.0 g of tetrahydrofuran-2-carboxylic acid chloride are added dropwise. The suspension is stirred at 0 ° C. for two hours, then the solvent is distilled off under vacuum. 200 ml of methanol and 200 ml of acetone become the residue given; the resulting suspension is under for 1/2 hour Stirring stirred at reflux; then it is cooled to 0 ° C. The product is isolated by filtration; you get 78g moist terazosin base.

This is suspended in 400 ml of methanol and 400 ml of methylene chloride; with stirring, 23.8 g of a 20% solution added dropwise by hydrogen chloride in methanol. This creates a solution that is clearly filtered. It is under vacuum Selectively distilled off methylene chloride, which falls Product out. The suspension is 3 hours at room temperature stirred, then the product is by filtration isolated. 74 g of moist terazosin hydrochloride are obtained Methanol adduct, which is optionally dried at 50 ° C under vacuum can be; this gives 49.0 g of white crystal powder, about 1 mole of methanol per mole of terazosin hydrochloride contains. An additional purification of the methanol adduct is possible by recrystallization from methanol.

The process steps described so far correspond to Principle of that known from JP-A-05-78352 already mentioned Manufacturing process for what is referred to as "Type M" there Methanol adduct.

2. Preparation of the crystalline polymorph.

10g of the crystalline adduct, the preparation of which above has been described in 100ml of ethanol containing 2-butanone is denatured, suspended. The suspension will heated with stirring and refluxed for 2 hours Ethanol kept, the reflux temperature for example Can be 78 ° C - 80 ° C. Then the suspension cooled to 20 ° C. The product is filtered isolated and dried at 50 ° C under vacuum. You get 8.4g crystal powder, its powder X-ray diffraction spectrum is shown in the figure. A determination the residual solvent content shows that the crystal powder typically less than 100 ppm methanol and contains less than 100ppm ethanol.

The methanolate to be treated with the polar solvent of the terazosin monohydrochloride is in the polar solvent only slightly soluble. The amount of used polar solvent is dimensioned so that as little as possible of the methanolate goes into solution, so that the far predominant amount of the product to be treated as a suspension is present in the polar solvent. This has essentials Advantages for carrying out the process, in particular for the recovery of the solid product simple mechanical separation, e.g. Filter. The treatment in the polar solvent is preferably at an elevated temperature.

The crystal form of the product obtained by the process is due to the powder X-ray diffraction spectrum shown in the figure characterized. This contains characteristic Peaks at the following, given in degrees Values of 2 : 7.04; 10.30; 12.02; 14.12; 14.44; 20.34; 22.34; 22.62; 23.58; 24.28 and 26.96, (all values ± 0.2).

The invention is not described in detail Embodiment limited. In particular, can as a polar solvent with which the crystalline methanolate of the terazosin hydrochloride is treated, any solvent from the group of alcohols with two to six Carbon atoms or ketones with three to six carbon atoms, or a mixture of two or more of these Solvents.

Claims (3)

1. A method of preparing a crystalline anhydrous polymorph of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2-tetrahydrofuroyl)-piperazine-monohydrochloride (terazosin-monohydrochloride) of the crystalline form IV, the powder X-ray diffraction spectrum of which has characteristic peaks at the following values of 2  (in angular degree): 7.04; 10.30; 12.02; 14.12; 14.44; 20.34; 22.34; 22.62; 23.58; 24.28; 26.96; each value + 0.2, characterised by the following steps:

   preparing the crystalline adduct from terazosin-monohydrochloride and methanol;

   treating the crystalline adduct in suspension with a polar solvent, selected from the group of alcohols having two to six carbon atoms, the ketones having three to six carbon atoms, or a mixture thereof,

   isolating the solid product from the suspension,

   wherein the treatment in suspension takes place at a raised temperature which is chosen to be sufficiently high that the crystalline form IV is formed.
2. A method according to Claim 1, characterised in that the solvent is ethanol and the high temperature is at least 78°C.
3. A method according to Claim 1 or 2, characterised in that the treatment time is at least 1 hour, preferably approximately 2 hours.

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